The present invention relates to a process for the preparation of indole derivatives and to novel intermediates.
Indole derivatives of the formula (1) hereinbelow are known as pharmaceutical active ingredients (e.g. from U.S. Pat. No. 4,739,073). Fluvastatin, an HMG-CoA reductase inhibitor, that is, a cholesterol-biosynthesis inhibitor, is an important indole derivative that is used in the treatment of hyperlipoproteinaemia and arteriosclerosis.
Known processes for the preparation of the indole compounds of formula (1) do not in all cases meet the demands made in terms of yield and economy of the process.
It is accordingly the aim of the present Application to make available a novel process for the preparation of indole compounds of formula (1) by means of which such compounds can be obtained in as high a yield as possible.
The present invention thus relates to a process for the preparation of compounds of formula 
wherein R1 is C1-C6alkyl and
X is hydrogen, a hydrocarbon radical or a cation,
in which process a compound of formula 
wherein R1 is as defined above and R2 is hydrogen or a hydrocarbon radical, is reduced, the resulting compound of formula 
wherein R1 and R2 are as defined above, is reacted with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR3 wherein R3 has the meanings given above for R2, and the resulting compound of formula 
is reduced and optionally hydrolysed.
There come into consideration as C1-C6alkyl radicals for R1, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, and straight-chain or branched pentyl or hexyl. C1-C4Alkyl radicals are preferred. R1 is preferably propyl, especially isopropyl.
There come into consideration as hydrocarbon radicals for R2, R3 and X, each independently of the others, for example unsubstituted or substituted alkyl, alkenyl, alkynyl and phenyl radicals. Special mention may be made of unsubstituted or substituted C1-C12alkyl, C3-C12-alkenyl, C3-C12alkynyl and phenyl radicals. Preferably, R2, R3 and X are each independently of the others unsubstituted or substituted alkyl radicals, especially C1-C12alkyl radicals and preferably C1-C6alkyl radicals. There may be mentioned as an example of substituents of the alkyl radicals, for example, phenyl that is unsubstituted or further substituted on the phenyl ring by nitro or by hydroxy. There may be mentioned as examples of R2, R3 and X methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, allyl, benzyl, nitrobenzyl and also hydroxybenzyl. R2, R3 and X are especially preferably C1-C4alkyl. R2 is more especially preferably methyl or ethyl, especially methyl. R3 and X are more especially preferably butyl, especially tert-butyl.
When the radical X is a cation, it may be, for example, sodium or potassium, especially sodium.
The reduction of the compound of formula (2) to the compound of formula (3) can be carried out according to commonly used methods, such as are described, for example, in Houben-Weyl, Methoden der organischen Chemie, Volume 7/2b, pages 1991 ff, Georg Thieme Verlag, Stuttgart, 1976. The reduction can be effected, for example, with a metal hydride, such as lithium aluminium hydride, diisobutylaluminium hydride or, especially, sodium borohydride, in an anhydrous, inert organic solvent, for example an ether, such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or 1,2-diethoxyethane. When sodium borohydride is used, it is preferable to use as solvent a mixture of such ethers with a lower alcohol, especially methanol. There comes into consideration as the temperature for the reaction, for example, a range of from xe2x88x9280 to 25xc2x0 C. Preferably, the reaction is carried out in an inert gas atmosphere.
The reaction of the compound of formula (3) to form the compound of formula (4) can be carried out, for example, according to the procedure described in U.S. Pat. No. 4,870,199. For example a compound of formula CH3xe2x80x94COOR3, such as tert-butyl acetate, may be used as the compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR3, R3 having the meanings and preferred meanings mentioned above. The reaction is generally so carried out that, in the presence of a strong base, such as lithium diisopropylamide, a monoanion of the compound of formula CH3xe2x80x94COOR3 is formed. The reaction is usually performed in an anhydrous, inert organic solvent, for example an ether, such as diethyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane or, especially, tetrahydrofuran, the reaction generally being carried out in an inert gas atmosphere, at a temperature of from xe2x88x9280 to 25xc2x0 C. In a next step, the monoanion formed is reacted with the compound of formula (3), that reaction usually being performed in the same solvent and in an inert gas atmosphere, at a temperature of, for example, from xe2x88x9280 to 25xc2x0 C.
The reduction of the compound of formula (4) can be carried out, for example, by way of a cyclic boronate using sodium borohydride, as in O. Tempkin, Tetrahedron, Vol. 53, No. 31, 10659-10670 (1997). The reduction is effected, for example, in an ether and/or lower alcohol, such as tetrahydrofuran or methanol, at a temperature of, for example, from xe2x88x9250 to xe2x88x9280xc2x0 C. As borane there comes into consideration, for example, diethyl methoxyborane. The reduction can alternatively be carried out with diisobutylaluminium hydride or tributyltin hydride, as described in S. Kiyooka, Tetrahedron Letters, Vol. 27, No. 26, 3009-3012 (1986), or with zinc borohydride, as described in F. Kathawala, Helv. Chim. Acta, Vol. 69, 803-805 (1986). The reduction can also be carried out with NaBH4 in the presence of triethylboranes as complexing agents, as described in U.S. Pat. No. 4,739,073.
The hydrolysis of the compound obtained after reduction of the compound of formula (4) can be carried out, for example, by conventional basic hydrolysis of the ester. For that purpose, the compound obtained after reduction of the compound of formula (4) is treated with approximately one mole of an inorganic base, such as an alkali metal hydroxide, for example potassium hydroxide or, especially, sodium hydroxide, in a mixture of water and a water-miscible organic solvent, for example a lower alcohol or an ether, such as methanol, ethanol or tetrahydrofuran, at a temperature of, for example, from 0 to 80xc2x0 C. It is also possible to proceed with slightly less than the stoichiometric amount of base and then remove excess ester by means of extraction with a water-immiscible organic solvent, for example tert-butyl methyl ether; freeze-drying can then be carried out. In order to form the free acid, the ester can also be hydrolysed in an acidic medium, it being possible for such a hydrolysis to be carried out according to procedures known per se. It is preferable, following the reduction of the compound of formula (4), for hydrolysis, preferably with sodium hydroxide, to be carried out.
The compounds of formula (2) are novel and can be obtained, for example, according to the following processes:
According to a process variant a) for the preparation of compounds of formula (2), a compound of formula 
wherein R1 has the meanings and preferred meanings given hereinbefore and Y is bromine, chlorine, iodine, xe2x80x94OSO2CF3 or xe2x80x94COCl, especially bromine,
is reacted with a compound that introduces the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94Z, wherein
Z is the radical xe2x80x94COOR4, xe2x80x94COR5 or xe2x80x94CN, R4 is hydrogen or a hydrocarbon radical and R5 is a hydrocarbon radical or unsubstituted or substituted amino,
and the resulting compound of formula 
optionally after conversion of the compound of formula (6) wherein Z is the radical xe2x80x94COOR4 into the corresponding acid chloride or into the free acid,
is reacted with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR2.
When R4 and R5 are hydrocarbon radicals, the meanings and preferred meanings for hydrocarbon radicals given hereinbefore for R2 apply. For R5 as unsubstituted or substituted amino there comes into consideration, for example, amino substituted by C1-C12alkyl and/or by C1-C12alkoxy. In that case there preferably comes into consideration a radical of formula xe2x80x94N(OR6)R7 wherein R6 and R7 are hydrogen or hydrocarbon radicals, especially C1-C6alkyl and preferably methyl.
When R6 and R7 are hydrocarbon radicals, the meanings and preferred meanings for hydrocarbon radicals given hereinbefore for R2 apply.
Preferred as radicals Z are the radicals of formula xe2x80x94COOR4 or xe2x80x94COxe2x80x94N(OR6)R7 wherein R4, R6 and R7 have the meanings and preferred meanings given hereinbefore.
The compounds of formulae 
are therefore of particular importance as compounds of formula (6).
The reaction of the compound of formula (5) to form the compound of formula (6) can be carried out according to methods known per se. The process can be carried out, for example, by the so-called Heck reaction, in which especially aromatic iodine or bromine compounds are reacted with olefins in the presence of palladium catalysts. The methodology is described, for example, in R. F. Heck, Acc. Chem. Res. 1979, 12,146; R. F. Heck, Org. React. 1982, 27, 345; and in R. F. Heck, Palladium Reactions in Synthesis, Academic Press, London 1985, S. Brxc3xa4se and A. De Meijere in Metal-catalyzed Cross-coupling Reactions, Chapter 3, Wiley-VCH, DE-Weinheim 1998 and in WO-A-99/47474.
There come into consideration as palladium catalysts especially those described under the general formula (Vlla) in WO-A-99/47474, preferably the catalysts denoted K1 to K11 in the examples documented in that specification, it being possible for the catalysts to be used especially in the amounts indicated therein.
As compounds that introduce the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94Z wherein Z is xe2x80x94COOR4 there come into consideration, for example, those of formula CH2xe2x95x90CHxe2x80x94COOR4, for example acrylic acid. As compounds that introduce the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94Z wherein Z is xe2x80x94COxe2x80x94N(OR6)R7 there come into consideration, for example, those of formula CH2xe2x95x90CHxe2x80x94COxe2x80x94N(OR6)R7, for example N-methoxy-N-methylacrylamide. Mention may also be made of the compound of formula CH2xe2x95x90CHxe2x80x94CN as compound that introduces the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94Z.
The molar ratio of the reaction partners (compound of formula (5)/compound introducing the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94Z) of such coupling reactions is generally in the range from 1:1 to 1:10, with preference being given to a ratio in the range from 1:1 to 1:2. The reaction is carried out with cooling up to the boiling temperature of the solvent, especially at from room temperature up to the boiling temperature of the solvent (reflux conditions). Suitable solvents are customary, especially higher-boiling, solvents, for example non-polar aprotic solvents, e.g. xylene or toluene, or polar aprotic solvents, e.g. dimethylformamide, dimethoxyethane or dimethylacetamide. The reaction product (6) obtainable can be worked up and isolated in a manner known per se by means of customary purification methods, for example by removal of the solvent and subsequent separation procedures, for example fine distillation, recrystallisation, preparative thin-layer chromatography, column chromatography or preparative gas chromatography.
When, in the resulting compound of formula (6), Z is the radical xe2x80x94COOR4 and R4 is a hydrocarbon radical, that compound can subsequently be converted into the free acid by acid hydrolysis of the ester. If desired, that compound can be converted into the acid chloride before being further reacted. Both the acid hydrolysis and the conversion into the acid chloride can be effected in conventional manner according to known procedures.
The reaction of the compound of formula (6), especially the compound of formula (7), with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR2 can be carried out, for example, as described in A. Nudelman, Synthesis, No. 4, 568-570 (1999). The conversion of the compound of formula (6) into the acid chloride and the reaction with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR2 can be carried out, for example, as in W. Wierenga, J. Org. Chem., Vol. 44, No. 2, 310-311 (1979). As compounds that introduce the radical of formula xe2x80x94CH2xe2x80x94COOR2 there may be mentioned, for example, compounds of the formula HOOCxe2x80x94CH2xe2x80x94COOR2, such as monomethyl malonate or monoethyl malonate, such compounds being understood as including also salts thereof, for example the potassium salt.
The reaction of the compound of formula (6), especially of the compound of formula (8), with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR2 can be carried out, for example, analogously to the process described above for the reaction of the compound of formula (3) to form the compound of formula (4). As compounds that introduce the radical of formula xe2x80x94CH2xe2x80x94COOR2 there may be mentioned in that connection, for example, compounds of the formula CH3xe2x80x94COOR2, such as ethyl acetate. A typical reaction by means of a Claisen reaction is described in J. A. Turner, J. Org. Chem., Vol. 54, 4229-4231 (1989).
The compound of formula (5) can be obtained, for example, by halogenating a corresponding compound in which Y is hydrogen. The halogenation can be carried out according to generally known methods. For the bromination, reference is made, for example, to Houben-Weyl, Methoden der organischen Chemie, Volume 5/4, pages 233 if, Georg Thieme Verlag, Stuttgart, 1960. There come into consideration for the bromination, for example, elemental bromine, N-bromosuccinimide, pyridinium bromide perbromide or triphenylphosphine dibromide, in an inert, preferably halogenated solvent, such as carbon tetrachloride, chloroform, chlorobenzene or dichlorobenzene. The bromination is generally carried out at a temperature of from xe2x88x925 to 25xc2x0 C., and in the case of N-bromosuccinimide at approximately from 40 to 85xc2x0 C.
The starting compounds wherein Y is hydrogen are known or can be obtained analogously to known procedures, for example the procedures indicated in U.S. Pat. No. 4,739,073.
According to a further process variant b) for the preparation of compounds of formula (2), a compound of formula 
is reacted with a compound of formula CH3xe2x80x94COxe2x80x94CH2xe2x80x94COOR2 and, optionally, then with a compound that introduces a protecting group, to form a compound of formula 
wherein R1 and R2 have the meanings and preferred meanings indicated hereinbefore and R8 and R9 are hydrogen or a protecting group,
a double bond is introduced under acidic or basic conditions, and any protecting group that may be present is removed.
As compounds that introduce a protecting group it is possible to use the compounds customary for that purpose, such as, for example, compounds that form readily removable esters or carbonates. Examples include acid anhydrides of formula (R10xe2x80x94CO)2O and acid chlorides of formula R10xe2x80x94COxe2x80x94CI, wherein R10 is C1-C4alkyl or C1-C4alkoxy.
R8 and R9 are preferably each independently of the other hydrogen, C1-C4alkylcarbonyl or C1-C4alkoxycarbonyl, especially hydrogen, acetyl or ethoxycarbonyl.
The reaction of a compound of formula (9) with a compound of formula CH3xe2x80x94COxe2x80x94CH2xe2x80x94COOR2 is effected, for example, by formation of the dianion of the latter compound by means of a strong base, and reaction of the dianion with a compound of formula (9). There come into consideration as strong bases, for example, n-butyllithium, lithium diisopropylamide and sodium hydride. Sodium hydride forms only the monoanion, with the result that, when it is used, a further base, such as n-butyllithium or lithium diisopropylamide, is used for the formation of the dianion from the monoanion. The reactions as a whole can be carried out at a temperature of from xe2x88x9280 to 25xc2x0 C. in an anhydrous, inert organic solvent, such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, in an inert gas atmosphere. The compound so obtained can be intercepted using a readily removable protecting group and then the double bond can be introduced under acidic or basic conditions in an inert solvent, such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene. The protected enol can then be hydrolysed likewise under basic or acidic conditions. It is also possible to hydrolyse the intermediate dianion and eliminate the alcohol under acidic conditions.
According to a further process variant c) for the preparation of compounds of formula (2), a compound of formula 
is reacted with a compound of formula 
to form a compound of formula 
and that compound is reacted with a compound that introduces the radical of formula xe2x80x94CH2xe2x80x94COOR2 wherein R1 and R2 have the meanings and preferred meanings given hereinbefore, R6 and R7 are hydrogen or hydrocarbon radicals, R11 is C1-C4alkyl or phenyl, especially methyl or ethyl, preferably ethyl, Ph is phenyl and Anxe2x88x92 is an anion.
R6 and R7 have the meanings and preferred meanings indicated hereinbefore. R6 and R7 are preferably C1-C6alkyl, especially methyl or ethyl, preferably methyl.
In the compound of formula (11b), there comes into consideration as anion especially halogen, such as bromine or preferably chlorine.
The reaction of the compound of formula (9) with a compound of formula (11a) or (11b) is generally carried out in the presence of a base, such as n-butyllithium or especially sodium hydride, in an organic solvent, such as an ether, for example diethyl ether or tetrahydrofuran, at a temperature of, for example, from xe2x88x9210 to 30xc2x0 C. Corresponding reactions are described in J. Boutagy, Chemical Reviews, Vol. 74, No. 1, 87-99 (1974).
It is preferable in this process variant to carry out the reaction of a compound of formula (9) with a compound of formula (11a).
The reaction of the compound of formula (8) to form the compound of formula (2) can be carried out as described hereinabove.
For the preparation of compounds of formula (2), preference is given to process variants a) and b), especially process variant a).
The compounds of formula (3) may be obtained in the form of a racemate or in the form of enantiomerically pure compounds of formula (3a) in the following (R) configuration 
or especially in the form of enantiomerically pure compounds of formula (3b) in the following (S) configuration 
The racemate can be resolved into the optically pure antipodes by means of known methods for the separation of enantiomers, for example by means of preparative chromatography using chiral supports (HPLC) or by esterification and crystallisation out using optically pure precipitating agents, for example D-(xe2x88x92) or L-(xe2x88x92)-mandelic acid or (+)- or (xe2x88x92)-10-camphor-sulfonic acid.
Enantiomerically pure or stereoisomerically pure compounds are to be understood here and hereinafter as compounds that are in at least 60%, especially 80% and, preferably, 90% pure form. Especially preferably they are in at least 95%, preferably 97.5% and, especially, 99% enantiomerically pure or stereoisomerically pure form.
The compounds of formula (1) may be obtained in the form of a mixture of stereoisomers or in pure form, especially in the following (3R,5S) configuration: 
Further stereoisomers that may be mentioned are those of the corresponding (3R,5R), (3S,5S) and (3S,5R) configurations.
Stereoisomerically pure compounds of formula (1), such as those of formula (1a), can be obtained according to procedures known for that purpose. Racemate cleavage can be carried out as indicated above under formulae (3a) and (3b).
The present invention relates also to the novel compounds of formulae (2), (3), (5) and (8), to processes for the preparation thereof, and also to the use of compounds of formula (2), (3), (5) or (8) as intermediates in the preparation of compounds of formula (1). The present invention relates also to the use of compounds of formula (5) or (8) as intermediates in the preparation of compounds of formula (2).
The preferred meanings mentioned hereinabove apply to the novel compounds of formulae (2), (3), (5) and (8).
As process for the preparation of compounds of formula (2) there comes into consideration, for example, the preparation according to process variant a), b) or c), especially according to process variant a) or b), preferably according to process variant a).
As process for the preparation of compounds of formula (3) there comes into consideration, for example, the reduction of the compound of formula (2). Preferably, the preparation of the compound of formula (2) is in that case carried out according to process variant a), b) or c), especially according to process variant a) or b), preferably according to process variant a).
As process for the preparation of compounds of formula (5) there comes into consideration, for example, the above-described halogenation, especially bromination, of the corresponding compound wherein Y is hydrogen.
As process for the preparation of compounds of formula (8) there comes into consideration especially the reaction of a compound of formula (5) with a compound that introduces the radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94N(OR6)R7 or the reaction of a compound of formula (9) with a compound of formula (11a) or (11b), preference being given to the first-mentioned reaction.
The following Examples illustrate the invention: